Summary,Project1 Trachealesophagealbirthdefects(TEDs)occurwhentheseparationofthetracheaandesophagusfromthe common foregut is disrupted during early fetal development. TEDs often present at birth without a prenatal diagnosisandifleftuncorrected,TEDsdisruptproperbreathingand/orfeedingandareusuallylifethreatening. Even when corrected surgically, they are often associated with long-term comorbidity. Although there is compellingevidenceforamajorgeneticcomponent,theetiologyofTEDsislargelyunknown.About40candidate mutationshavebeenassociatedwithTEDswithvaryingdegreesofconfidence,butonlyadozenofthesegenes have been validated in animal models and even then the development mechanisms they regulate are poorly understood.OurPremiseisthatthereareuniqueunstudiedgeneticmutationsthatcauseTEDsandthat theseactindistinctdevelopmentalpathwaystodeterminetheTEDanatomicandhistologicalphenotype andultimatelytheclinicaloutcomeofthesepatients.OurunderstandingoftheclinicalpathologyofTEDs has been hampered by the lack of a detailed large scale genetic, anatomic, and clinical investigation of this patientpopulation.Therefore,theprimarygoalofthisprojectistoimproveourunderstandingofthegeneticand anatomic basis of tracheal esophageal birth defects (TEDs) in order to enhance diagnosis, determine factors that influence prognosis and advance treatment strategies. The second goal is to serve as catalyst for the developmentalbiologystudiesinprojects2and3throughthecreationofacomprehensivedatabasethatwill integratehistologicalandanatomicphenotype,genotype,andclinicaloutcomedata. Aim1:IdentifycandidatecausativemutationsinpatientswithTEDsusingtriogenomicsequencingofTED patientsandtheirparents. Aim 2: Investigate the esophageal, tracheal, mediastinal and pulmonary anatomy in patients with TEDs beforeandaftersurgicalrepair. Aim3:Createamulti-centerTEDregistrythatintegratesadetaileddescriptionoftheclinicalandanatomic phenotype,genotype,surgicalrepairstrategy,andlongtermclinicaloutcomeinTEDpatients.